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Calcium-dependent inactivation terminates calcium release in skeletal muscle of amphibians.

Ríos E, Zhou J, Brum G, Launikonis BS, Stern MD - J. Gen. Physiol. (2008)

Bottom Line: In groups of thousands of sparks occurring spontaneously in membrane-permeabilized frog muscle cells a complex relationship was found between amplitude a and rise time T, which in sparks corresponds to the active time of the underlying Ca2+ release.Biophys.Considering these results and other available evidence it is concluded that Ca2+-dependent inactivation, or CDI, provides the crucial mechanism for termination of sparks and cell-wide Ca2+ release in amphibians.

View Article: PubMed Central - PubMed

Affiliation: Section of Cellular Signaling, Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612, USA.

ABSTRACT
In skeletal muscle of amphibians, the cell-wide cytosolic release of calcium that enables contraction in response to an action potential appears to be built of Ca2+ sparks. The mechanism that rapidly terminates this release was investigated by studying the termination of Ca2+ release underlying sparks. In groups of thousands of sparks occurring spontaneously in membrane-permeabilized frog muscle cells a complex relationship was found between amplitude a and rise time T, which in sparks corresponds to the active time of the underlying Ca2+ release. This relationship included a range of T where a paradoxically decreased with increasing T. Three different methods were used to estimate Ca2+ release flux in groups of sparks of different T. Using every method, it was found that T and flux were inversely correlated, roughly inversely proportional. A simple model in which release sources were inactivated by cytosolic Ca2+ was able to explain the relationship. The predictive value of the model, evaluated by analyzing the variance of spark amplitude, was found to be high when allowance was made for the out-of-focus error contribution to the total variance. This contribution was estimated using a theory of confocal scanning (Ríos, E., N. Shirokova, W.G. Kirsch, G. Pizarro, M.D. Stern, H. Cheng, and A. González. Biophys. J. 2001. 80:169-183), which was confirmed in the present work by simulated line scanning of simulated sparks. Considering these results and other available evidence it is concluded that Ca2+-dependent inactivation, or CDI, provides the crucial mechanism for termination of sparks and cell-wide Ca2+ release in amphibians. Given the similarities in kinetics of release termination observed in cell-averaged records of amphibian and mammalian muscle, and in spite of differences in activation mechanisms, CDI is likely to play a central role in mammals as well. Trivially, an inverse proportionality between release flux and duration, in sparks or in global release of skeletal muscle, maintains constancy of the amount of released Ca2+.

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Model prediction of spark amplitudes. A, dots represent a vs. T for the first set of experimental sparks (as in Fig. 1 A). Circles represent their bin averages (as in Fig. 1 B). The curve in blue plots a as a function of T, calculated with “model 1,” that is, Eqs. 9 and 6, with parameter values given in the legends of Figs. 4 and 5. The curve in red is by “model 2,” for which m3 is assumed constant (37 pA) at T < 4.4 ms. Note that in this range of T the a(T) dependence is exponential, given by Eq. 7 scaled by 37/30. (B) Bin-averaged experimental a (circles), prediction by models 1 (blue line) and 2 (red), plotted as a function of both T (as in A) and m3. The plot illustrates the model calculation of a, which relies on the bijective correspondence between T and m3 given by Eq. 6.
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fig6: Model prediction of spark amplitudes. A, dots represent a vs. T for the first set of experimental sparks (as in Fig. 1 A). Circles represent their bin averages (as in Fig. 1 B). The curve in blue plots a as a function of T, calculated with “model 1,” that is, Eqs. 9 and 6, with parameter values given in the legends of Figs. 4 and 5. The curve in red is by “model 2,” for which m3 is assumed constant (37 pA) at T < 4.4 ms. Note that in this range of T the a(T) dependence is exponential, given by Eq. 7 scaled by 37/30. (B) Bin-averaged experimental a (circles), prediction by models 1 (blue line) and 2 (red), plotted as a function of both T (as in A) and m3. The plot illustrates the model calculation of a, which relies on the bijective correspondence between T and m3 given by Eq. 6.

Mentions: Fig. 6 A reproduces the scatter plot (a vs. T) of all events in Fig. 1 A, plus the bin averages of Fig. 1 B. In blue is the predicted amplitude, computed using Eq. 8, that is(9)\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}a_{s}(T,m_{3}(T))=\frac{{\phi}\hspace{.167em}m_{3}(T)}{30}be^{-kT},\end{equation*}\end{document}where m3(T) is the functional inverse of Eq. 6, obtained numerically, and φ, 1.9, was determined for best fit of the decaying portion of the bin-averaged plot. It should be clear at this point that the model (named “model 1”) reproduces well the observed a vs. T, but only in the range where this relationship is decreasing. Clearly, model 1 does not work at lower values of T.


Calcium-dependent inactivation terminates calcium release in skeletal muscle of amphibians.

Ríos E, Zhou J, Brum G, Launikonis BS, Stern MD - J. Gen. Physiol. (2008)

Model prediction of spark amplitudes. A, dots represent a vs. T for the first set of experimental sparks (as in Fig. 1 A). Circles represent their bin averages (as in Fig. 1 B). The curve in blue plots a as a function of T, calculated with “model 1,” that is, Eqs. 9 and 6, with parameter values given in the legends of Figs. 4 and 5. The curve in red is by “model 2,” for which m3 is assumed constant (37 pA) at T < 4.4 ms. Note that in this range of T the a(T) dependence is exponential, given by Eq. 7 scaled by 37/30. (B) Bin-averaged experimental a (circles), prediction by models 1 (blue line) and 2 (red), plotted as a function of both T (as in A) and m3. The plot illustrates the model calculation of a, which relies on the bijective correspondence between T and m3 given by Eq. 6.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2279174&req=5

fig6: Model prediction of spark amplitudes. A, dots represent a vs. T for the first set of experimental sparks (as in Fig. 1 A). Circles represent their bin averages (as in Fig. 1 B). The curve in blue plots a as a function of T, calculated with “model 1,” that is, Eqs. 9 and 6, with parameter values given in the legends of Figs. 4 and 5. The curve in red is by “model 2,” for which m3 is assumed constant (37 pA) at T < 4.4 ms. Note that in this range of T the a(T) dependence is exponential, given by Eq. 7 scaled by 37/30. (B) Bin-averaged experimental a (circles), prediction by models 1 (blue line) and 2 (red), plotted as a function of both T (as in A) and m3. The plot illustrates the model calculation of a, which relies on the bijective correspondence between T and m3 given by Eq. 6.
Mentions: Fig. 6 A reproduces the scatter plot (a vs. T) of all events in Fig. 1 A, plus the bin averages of Fig. 1 B. In blue is the predicted amplitude, computed using Eq. 8, that is(9)\documentclass[10pt]{article}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{pmc}\usepackage[Euler]{upgreek}\pagestyle{empty}\oddsidemargin -1.0in\begin{document}\begin{equation*}a_{s}(T,m_{3}(T))=\frac{{\phi}\hspace{.167em}m_{3}(T)}{30}be^{-kT},\end{equation*}\end{document}where m3(T) is the functional inverse of Eq. 6, obtained numerically, and φ, 1.9, was determined for best fit of the decaying portion of the bin-averaged plot. It should be clear at this point that the model (named “model 1”) reproduces well the observed a vs. T, but only in the range where this relationship is decreasing. Clearly, model 1 does not work at lower values of T.

Bottom Line: In groups of thousands of sparks occurring spontaneously in membrane-permeabilized frog muscle cells a complex relationship was found between amplitude a and rise time T, which in sparks corresponds to the active time of the underlying Ca2+ release.Biophys.Considering these results and other available evidence it is concluded that Ca2+-dependent inactivation, or CDI, provides the crucial mechanism for termination of sparks and cell-wide Ca2+ release in amphibians.

View Article: PubMed Central - PubMed

Affiliation: Section of Cellular Signaling, Department of Molecular Biophysics and Physiology, Rush University, Chicago, IL 60612, USA.

ABSTRACT
In skeletal muscle of amphibians, the cell-wide cytosolic release of calcium that enables contraction in response to an action potential appears to be built of Ca2+ sparks. The mechanism that rapidly terminates this release was investigated by studying the termination of Ca2+ release underlying sparks. In groups of thousands of sparks occurring spontaneously in membrane-permeabilized frog muscle cells a complex relationship was found between amplitude a and rise time T, which in sparks corresponds to the active time of the underlying Ca2+ release. This relationship included a range of T where a paradoxically decreased with increasing T. Three different methods were used to estimate Ca2+ release flux in groups of sparks of different T. Using every method, it was found that T and flux were inversely correlated, roughly inversely proportional. A simple model in which release sources were inactivated by cytosolic Ca2+ was able to explain the relationship. The predictive value of the model, evaluated by analyzing the variance of spark amplitude, was found to be high when allowance was made for the out-of-focus error contribution to the total variance. This contribution was estimated using a theory of confocal scanning (Ríos, E., N. Shirokova, W.G. Kirsch, G. Pizarro, M.D. Stern, H. Cheng, and A. González. Biophys. J. 2001. 80:169-183), which was confirmed in the present work by simulated line scanning of simulated sparks. Considering these results and other available evidence it is concluded that Ca2+-dependent inactivation, or CDI, provides the crucial mechanism for termination of sparks and cell-wide Ca2+ release in amphibians. Given the similarities in kinetics of release termination observed in cell-averaged records of amphibian and mammalian muscle, and in spite of differences in activation mechanisms, CDI is likely to play a central role in mammals as well. Trivially, an inverse proportionality between release flux and duration, in sparks or in global release of skeletal muscle, maintains constancy of the amount of released Ca2+.

Show MeSH
Related in: MedlinePlus